Acid/base and H+/OH- permeabilities will be studied in lipid bilayer membranes, which are used as models for biological membranes. Planar bilayers will be made by the brush (Mueller-Rudin) technique or by the monolayer (Montal-Mueller) technique. Unilamellar liposomes will be prepared by detergent dialysis in a Lipoprep apparatus. H+/OH- and acid/base transport will be measured by means of radiotracer, pH electrode and electrical techniques. The objectives of six interrelated projects are as follows: First, H+/OH- permeabilities will be measured as a function of lipid composition and pH, and specific agents suspected to increase H+ or OH- permeability will be tested, e.g., fatty acids, organometal ions, halogenated anesthetics, detergents and lipid oxidation products. Second, the permeabilities of fatty acids through lipid bilayers will be studied as a function of acyl chain length in order to test Overton's rule in the unexplored range of medium to long-chain fatty acids. The ability of micelles and protein to facilitate fatty acids diffusion through the aqueous unstirred layers will be investigated in order to gain insights into mechanisms of uptake by intestines and other tissues. Third, the permeabilities of HSCN/SCN-, HCNO/CNO-, HNO2/NO-2, and NH3/NH+4 will be studied in order to explain the mechanisms by which these acids and bases inhibit gastric acid secretion. Fourth, a simple electrical method for measuring weak acid/base permeability will be developed, utilizing proton ionophores to measure the rate of acid/base diffusion through membranes. This method will then be used to study permeability to NH3 and various primary, secondary and tertiary amines which will be utilized as probes of membrane structure in the following two projects. Fifth, the "solubility-diffusion" and "interfacial kinetics" models of nonelectrolyte transport will be compared and tested for polar and nonpolar molecules of varying sizes and shapes. In order to identify the rate-limiting barrier(s), permeabilities will be studied in membranes which differ with respect to polar head group, hydrocarbon thickness or hydrocarbon structure. Sixth, the "liquid hydrocarbon" and "polymer" models of membranes structure will be compared by studying permeability patterns of acids and bases which vary widely in size, shape and hydrophobicity. The results of these projects will increase our understanding of the mechanisms of acid/base and nonelectrolyte transports through lipid bilayers and biological membranes.